The process linking excitation to contraction in cardiac muscle is complex, possibly involving two or more coupling mechanisms acting on as many as five separate Ca compartments. To understand the process fully, it is necessary to be able to separate these individual processes through the use of various physiologic or pharmacologic inhibitors. However, inhibitors of excitation-contraction coupling have not been fully characterized. This research proposes to examine more fully the nature of the negative inotropic actions of several clinically useful agents. The role of the sarcolemma will be differentiated from that of intracellular organelles as a site of drug action through the use of mechanically disaggregated, hyperpermeable muscle fragments and other standard techniques. The research to date has focused on the actions of quinidine. The results suggest that quniidine exerts its negative inotropic effects through its actions on Na metabolism by the sarcolemma; actions on intracellular organelles are apparently not involved. The results further suggest that the negative inotropic actions of quinidine may be obscured, under certain conditions, by a countervailing positive inotropic action which may result from an alpha adrenergic stimulant action of quinidine.